Cell signaling through growth factor receptors and protein kinases is an important regulator of cell growth, proliferation and differentiation. In normal cell growth, factors (i.e. PDGF or EGF and others), through receptor activation (i.e. ErbB2, EGFR, PDGFR), activate MAP (Mitogen-activating protein) kinase pathways. One of the most important and most well understood MAP kinase pathways involved in normal and uncontrolled cell growth is the Ras/Raf/Mek/Erk kinase pathway. In proliferative diseases, genetic mutations and/or overexpression of the growth factor receptors, downstream signaling proteins, or protein kinases involved in the kinase pathway lead to uncontrolled cell proliferation and, eventually, tumor formation. For example, some cancers contain mutations which results in the activation of this pathway due to continuous production of growth factors. The statistics show that mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers. Recently, bRaf mutations have been identified in more than 60% of malignant melanoma. Studies of primary tumor samples and cell lines have also shown constitutive or overactivation of the Ras/Raf/Mek/Erk pathway in cancers of pancreas, colon, lung, ovary and kidney.
As constitutive or overactivation of MAP kinase cascade plays a pivotal role in cell proliferation and differentiation, inhibition of this pathway is believed to be beneficial in hyperproliferative diseases. Mek is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates for Mek phosphorylation are the MAP kinases, Erk 1 and 2. Hence, inhibition of MEK would block Ras/Raf/Mek/Erk pathway and result in cell growth inhibition, especially the cell growth due to the overactivation of Ras or Raf. Meanwhile Mek is also related to inflammatory disease and symptoms, including acute and chronic inflammation.
Inhibitors of Mek have shown some effects in clinical experiments of nude mice. Recently, some Mek inhibitors have been applied at clinical experiments of people. Therefore, Mek is a potential new target and more and more Mek inhibitors are developed and reported, for example, WO 98/43960; WO 99/01421; WO 99/01426; WO 00/41505; WO 00/42002; WO 00/41003; WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO 03/077914; WO 03/077855; WO 03/077914; WO 05/023251; WO 05/023759; WO 05/051300; WO 05/051301; WO 05/051302; WO 05/051906; WO 05/000818; WO 05/007616; WO 05/009975; WO 05/046665; WO 06/134469; WO 07/044,084; WO 07/014,011; WO 07/121,269; WO 07/121,481; WO 07/071,951; WO 07/044,515; WO 08/021,389; WO 08/076,415; WO 08/089,459; WO 08/078,086; WO 08/120,004; WO 08/124,085; WO 08/125,820; WO 09/018,238; WO 09/074,827; WO 09/013,426; WO 09/093,008; WO 09/093,009; WO 09/093,013; WO 09/153,554 and so on.
However, many known MEK inhibitors suffer from weak inhibitory activity, intolerable toxicity or lack of desirable pharmaceutical properties. Thus, there remains a need for potent inhibitors of MEK with appropriate pharmaceutical properties for clinical applications.